Genetic Evidence of Causal Relation Between Intestinal Glucose Absorption and Early Postprandial Glucose Response: A Mendelian Randomization Study

• Published in: Diabetes (New York, N.Y.) Vol. 73; no. 6; pp. 983 - 992
• Main Authors: Peschard, Simon, Raverdy, Violeta, Bauvin, Pierre, Goutchtat, Rebecca, Touche, Veronique, Derudas, Bruno, Gheeraert, Celine, Dubois-Chevalier, Julie, Caiazzo, Robert, Baud, Gregory, Marciniak, Camille, Verkindt, Helene, Oukhouya Daoud, Naima, Le Roux, Carel W., Lefebvre, Philippe, Staels, Bart, Lestavel, Sophie, Pattou, François
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.06.2024
• Subjects: Biopsy; Blood glucose; Diabetes; Diabetes mellitus (non-insulin dependent); Genetic analysis; Genetics/Genomes/Proteomics/Metabolomics; Genotyping; Glucose; Glucose tolerance; Haplotypes; Intestine; Risk factors; Sodium-glucose cotransporter; Statistical analysis
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db23-0805

The post-prandial glucose response is an independent risk factor for type 2 diabetes. Observationally, early glucose response after an oral glucose challenge has been linked to intestinal glucose absorption, largely influenced by the expression of sodium-glucose-co-transporter-1 (SGLT1). This study utilizes Mendelian randomization (MR) to estimate the causal effect of intestinal SGLT1 expression on early glucose response. Involving 1547 subjects with class II/III obesity from the ABOS cohort, the study employs SGLT1 genotyping, oral glucose tolerance tests, and jejunal biopsies to measure SGLT1 expression. A loss-of-function SGLT1 haplotype served as the instrumental variable, with intestinal SGLT1 expression as the exposure and the change in 30-minute post-load glycemia from fasting glycemia (Δ30 glucose) as the outcome. Results showed that 12.8% of the 1,342 genotyped patients carried the SGLT1 loss-of-function haplotype, associated with a mean Δ30 glucose reduction of -0.41 mmol/L and a significant decrease in intestinal SGLT1 expression. The observational study linked a one standard deviation decrease in SGLT1 expression to a Δ30 glucose reduction of -0.097 mM/L. MR analysis paralleled these findings, associating a statistically significant reduction in genetically instrumented intestinal SGLT1 expression with a Δ30 glucose decreases of -0.353. In conclusion, the MR analysis provides genetic evidence that reducing intestinal SGLT1 expression causally lowers early post-load glucose response. This finding has a potential translational impact on managing early glucose response in type 2 diabetes.